PROJECT SUMMARY/ABSTRACT In the cell, genetic information is tightly regulated and maintained through functions of the nuclear envelope (NE). The NE is composed of a double membrane and a network of proteins that sequester and protect the genome inside the nucleus, compartmentalized away from the bulk of cellular processes. One important function of the NE is to structurally shield the genome from physical forces. In addition, the NE controls the transport of material in and out of the nucleus and regulates gene expression by directing interactions between genes and proteins. Defects in NE protein expression alter NE organization, structure, and dynamics leading to changes in gene expression and genome instability. NE protein dysregulation is implicated in severe diseases including dilated cardiomyopathy, muscular dystrophy, progeria, and cancers. It was recently discovered that in some cancer cell types the NE can rupture and reseal during unexpected points of the cell cycle. Some cells undergo repeated NE rupture and repair events without a decrease in viability, and migrating cells routinely rupture and repair the NE. This discovery has altered the canonical model of the interphase NE and introduced a role for aberrant NE dynamics in the pathology of diseases like cancer. Despite its importance, the mechanisms that control NE dynamics and their dysregulation in disease are largely unknown. We hypothesize that NE rupture and repair mechanisms contribute to cancer by aiding the biomechanics of single cell migration. The goal of this project is to determine the molecular mechanisms underlying NE dynamics and address how changes in the organization or stability of the nuclear envelope relates to cancer development. We aim to: 1. Identify mechanisms of NE rupture and repair, 2. Determine the consequences of NE rupture and repair on the cell, and 3. Define the role of NE rupture and repair in cancer cell migration. Questions of why the NE ruptures and how it is repaired will be addressed using a cell-based model of this process and a live-cell imaging platform developed in the lab. We will refine the link between dynamic NE rupture and cancer by observing how rupture and repair affect cancer cell function, growth, and migration. Through this work we hope to identify the factors that control NE rupture and repair and uncover biomarkers for cancer cell progression with the ultimate goal of forestalling cancer progression and treating disease. Understanding the complex functions of the NE and its dysregulation will provide important clues about disease pathogenesis and human aging.